Curative chemotherapy regimens for Hodgkin's disease represent one of the major breakthroughs in clinical oncology. Multi-agent chemotherapy regimens have increased the cure rate to more than 80% for these patients Nevertheless, 3% of patients die from treatment-related causes, and for patients who do not respond to standard therapy or relapse after first-line treatment, the only available treatment modality is high-dose chemotherapy in combination with stem cell transplantation. This treatment is associated with an 80% incidence of mortality, significant morbidity and a five-year survival rate of less than 50% (See e.g., Engert, et al., 1999, Seminars in Hematology 36:282–289).
The primary cause for tumor relapse is the development of tumor cell clones resistant to the chemotherapeutic agents. Immunotherapy represents an alterative strategy which can potentially bypass resistance. Monoclonal antibodies for specific targeting of malignant tumor cells has been the focus of a number of immunotherapeutic approaches. For several malignancies, antibody-based therapeutics are now an acknowledged part of the standard therapy. The engineered anti-CD20 antibody Rituxan®, for example, was approved in late 1997 for the treatment of relapsed low-grade NHL.
CD30 is a 120 kilodalton membrane glycoprotein (Froese et al., 1987, J. Immunol. 139: 2081–87) and a member of the TNF-receptor superfamily. This family includes TNF-RI, TNF-RII, CD30, CD40, OX-40 and RANK, among others.
CD30 is a proven marker of malignant cells in Hodgkin's disease (HD) and anaplastic large cell lymphoma (ALCL), a subset of non-Hodgkin's (NHL) lymphomas (Dürkop et al., 1992, Cell 88:421–427). Originally identified on cultured Hodgkin's-Reed Steinberg (H-RS) cells using the monoclonal antibody Ki-1 (Schwab et al., 1982, Nature 299:65–67), CD30 is highly expressed on the cell surface of all HD lymphomas and the majority of ALCL, yet has very limited expression in normal tissues to small numbers of lymphoid cells in the perifollicular areas (Josimovic-Alasevic et al., 1989, Eur. J. Immunol. 19:157–162). Monoclonal antibodies specific for the CD30 antigen have been explored as vehicles for the delivery of cytostatic drugs, plant toxins and radioisotopes in both preclinical models and clinical studies (Engert et al., 1990, Cancer Research 50:84–88; Barth et al., 2000, Blood 95:3909–3914). In patients with HD, targeting of the CD30 antigen could be achieved with low doses of the anti-CD30 mAb, BerH2 (Falini et al., 1992, British Journal of Haematology 82:38–45). Yet, despite successful in vivo targeting of the malignant tumor cells, none of the patients experienced tumor regression. In a subsequent clinical trial, a toxin (saporin) was chemically conjugated to the antibody BerH2 and all four patients demonstrated rapid and substantial reductions in tumor mass (Falini et al., 1992, Lancet 339:1195–1196).
These observations underscore the validity of the CD30 receptor as a target antigen. However, all of the patients treated with the mAb-toxin conjugate developed antibodies to the toxin. One of the major limitations of immunotoxins is their inherent immunogenicity that results in the development of antibodies to the toxin molecule and neutralizes their effects (Tsutsumi et al., 2000, Proc. Nat'l Acad. Sci. U.S.A. 97:8545–8553). Additionally, the liver toxicity and vascular leak syndrome associated with immunotoxins potentially limits the ability to deliver curative doses of these agents (Tsutsumi et al., 2000, Proc. Nat'l Acad. Sci. U.S.A. 97:8545–8553).